Enalapril is an ACE inhibitor approved by the U.S. Food and Drug Administration (FDA) to treat high blood pressure in adults and children one month or older. Enalapril is also used to treat congestive heart failure in adults and to delay the onset of kidney failure in people with Alport syndrome.
How enalapril works
Enalapril works by blocking the activity of an enzyme called angiotensin-converting-enzyme (ACE). This enzyme normally converts a hormone called angiotensin 1 into another hormone called angiotensin 2. Angiotensin 2 breaks down a protein called bradykinin, which normally widens blood vessels and decreases blood pressure. The degradation of bradykinin leads to constricted blood vessels and increased blood pressure.
Angiotensin 2 itself is a vasoconstrictor, an agent that causes blood vessels to narrow, increasing blood pressure.
Finally, angiotensin 2 stimulates the release of a hormone called aldosterone. This hormone signals the kidney to increase the production of proteins, which increase sodium and water absorption from the urine in the kidneys before it is excreted.
Enalapril is a pro-drug; once ingested it is metabolized by the liver. The metabolized form of the treatment, called enalaprilat, competes for the active site of the ACE enzyme and therefore stops it from binding to angiotensin 1 and converting it to angiotensin 2. By reducing the levels of angiotensin 2, enalapril, therefore, reduces blood pressure through several mechanisms. Reduced blood pressure could decrease the strain on the kidneys and delay the development of end-stage kidney disease or kidney failure in Alport syndrome patients.
Enalapril in clinical trials
A small study published in the journal Pediatric Nephrology followed 10 children with Alport syndrome who received enalapril for five years. Nine were boys, eight of whom had X-linked Alport syndrome (XLAS). The other two patients had autosomal recessive Alport syndrome (ARAS). The starting dose of enalapril was 0.05 mg/kg of body weight; the target dose was 0.5 mg/kg of body weight per day. All patients showed a decrease in the level of protein in the urine, a sign of kidney problems, over the course of the study. However, three patients did not reach the target dose of enalapril because of orthostatic hypotension (dizziness upon standing). One of these three developed end-stage kidney disease within five years. The researchers concluded that enalapril reduces protein levels in the urine and may have a kidney-protective effect.
A Phase 3 clinical trial (NCT00568178), results of which were published in the journal Pediatric Nephrology compared losartan (an angiotensin 2 receptor blocker) to enalapril in 27 patients with Alport syndrome. Patients were randomized to receive either losartan (15 patients) or enalapril (12 patients). Patients were monitored for 12 weeks, looking at the levels of protein in their urine. Patients who saw a reduction in protein in their urine over the 12 weeks were invited to continue treatment for 36 months. Kidney function was monitored throughout the study. The incidence of adverse events was low and comparable in both treatment groups. In children with protein in the urine as a result of Alport syndrome, losartan maintained the reduction of protein in the urine seen during the 12-week study. Enalapril, on the other hand, produced further reductions over the 36-month study.
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